Clinical Significance of BCL2, C-MYC, and BCL6 Genetic Abnormalities, Epstein-Barr Virus Infection, CD5 Protein Expression, Germinal Center B Cell/Non-Germinal Center B-Cell Subtypes, Co-expression of MYC/BCL2 Proteins and Co-expression of MYC/BCL2/BCL6 Proteins in Diffuse Large B-Cell Lymphoma: A Clinical and Pathological Correlation Study of 120 Patients

Abstract

Background: Clinical significance of germinal center B-cell (GCB) and non-GCB sub-categorization, expression of MYC, BCL2, BCL6, CD5 proteins and Epstein Barr virus encoded RNA (EBER) positivity in diffuse large B-cell lymphoma (DLBCL) remain controversial. Could these biomarkers accurately identify high risk DLBCL patients? Are MYC, BCL2 and BCL6 proteins expression feasible as baseline testing to predict c-Myc , BCL2 or BCL6 gene rearrangements? Aims: To investigate prognostic values of GCB/non-GCB sub-categorization, Double Protein Expression Lymphoma (DPL), Triple Protein Expression Lymphoma (TPL), positivity of CD5 protein and EBER in patients with DLBCL disease. To evaluate correlation between BCL2 , c-Myc and BCL6 gene rearrangements with BCL2, MYC and BCL6 proteins expression. Methods: Diagnostic tissue samples of 120 DLBCL patients between January 2012 to December 2013 from four major hospitals in Malaysia were selected. Samples were subjected to immunohistochemical staining, fluorescent in-situ hybridization (FISH) testing, and central pathological review. Pathological data were correlated with clinical characteristics and treatment outcome. Results: A total of 120 cases were analysed. Mean age of diagnosis was 54.1 years ± 14.6, 64 were males, 56 were females, mean follow up period was 25 months (ranged from 1 to 36 months). Of the 120 cases, 74.2% were non-GCB whereas 25.8% were GCB, 6.7% were EBER positive, 6.7% expressed CD5 protein, 13.3% were DPL and 40% were TPL. The prevalence of c -Myc , BCL2, BCL6 gene rearrangements were 5.8%, 5.8%, and 14.2%, respectively; and 1.6% were Double Hit Lymphoma (DHL). EBER positivity, DPL, TPL, c -Myc gene rearrangement, BCL2 gene rearrangement, extra copies of BCL2 gene and BCL6 gene rearrangement were associated with shorter median overall survival (P<0.05). IPI score was the significant determinants of median overall survival in DPL and TPL (P<0.05). CD5 protein expression and GCB/non-GCB sub-categorization did not affect treatment outcome (P>0.05). Overall, c-Myc , BCL2 and BCL6 gene rearrangements showed weak correlation with expression of MYC, BCL2 and BCL6 proteins (P>0.05). Fluorescent in situ hybridization is the preferred technique for prediction of treatment outcome in DLBCL patients. Conclusion: c-Myc , BCL2 , and BCL6 gene rearrangements, EBER expression, DHL, TPL and IPI score are reliable risk stratification tools. MYC, BCL2 and BCL6 proteins expression are not applicable as baseline biomarkers to predict ...

The Incidence and Treatment Response of Double Expression of MYC and BCL2 in Patients with Diffuse Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis

“…IHC interpretation was performed by hematopathologists or other pathologists nearly three-quarters of the time (30/41, 73.2%). In brief, the study design was prospective in one study [59], retrospective in 22 [3,32,33,36,[38][39][40]42,[44][45][46][47][49][50][51]54,60,61,63,66,67,69], secondary analysis of primary clinical trials in six [37,41,48,53,57,58], and not-explained in 12 [19][20][21]34,35,43,52,55,56,62,65,68]. The number of patients per study ranged from 20 to 688, with median ages of 46-70 years.…”

The Spectrum of MYC Alterations in Diffuse Large B-Cell Lymphoma

“…In normal lymphoid cells, genetic insults or oxidative stress inhibits BCL2 to promote apoptosis by increasing the expression of proteins of the BH3 family. In malignant lymphoma cells, overexpression of BCL2 caused by chromosomal translocations and increased gene copy number suppresses the apoptosis and promotes the malignant proliferation of lymphoma cells and finally accelerates the MYC-induced lymphomagenesis [23, 24]. About 30% of DLBCL harbor both BCL2 and MYC overexpression, which is defined as double-expressor DLBCL (DE-DLBCL) [25].…”

Clinicopathological and genetic characteristics of diffuse large B‐cell lymphoma of the oropharyngeal and maxillofacial region

“…In the current study, the positive immunohistochemical staining of MYC protein was found to be a valuable predicting factor of DLBCL unfavorable prognosis through univariate and multivariate model analysis, which is consistent with previous studies (Kluk et al., 2012; Yan et al., 2014). Although a molecular study of DLBCL of the OMR was absent, studies of DLBCL in non‐specific position have demonstrated that BCL2 and MYC gene rearrangement, and double/triple‐hit lymphoma, predict a worse overall survival (Horn et al., 2013; Ting et al., 2019). In our study, BCL2 and MYC gene rearrangement, and double/triple‐hit DLBCL, correlated with a significantly lower overall survival rate in the univariate analysis, but no significance was found in the multivariate model.…”